Amlodipine, the IUPAC Name of
3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, is a long-acting calcium channel blocker useful in the treatment of cardiovascular diseases, such as angina pectoris, hypertension, congestive heart failure, etc.
Amlodipine is a racemic compound with a chiral center. In general, pure stereoisomers are known to have better therapeutic effects than racemic mixtures. Furthermore, chiral compounds tend to have different pharmacokinetic profiles, depending on the steric arrangement of the isomer compounds or their salts. There are two possible stereoisomers of amlodipine, because of its one chiral center, that is, R-(+)-amlodipine and (S-(−)-amlodipine, that are different from each other in pharmacokinetic profile. The R(+) isomer of amlodipine is a potent inhibitor of smooth muscle cell migration despite its lack of calcium channel-blocking activity (U.S. Pat. No. 6,080,761). It is useful for preventing and treating atherosclerosis. On the other hand, the (S)-(−)-isomer of amlodipine is a potent calcium channel blocker. For ideal use as a calcium channel blocker, amlodipine is administered in the form of S-(−)-amlodipine, substantially free of its (+) stereoisomer (U.S. Pat. No. 6,057,344). U.S. Pat. No. 6,291,490 also discloses S-(−)-amlodipine, teaching that S-(−)-amlodipine avoids the adverse effect of amlodipine in racemic mixtures.
European Patent Publication No. 89,167 discloses an acid adduct as an example of a pharmaceutically acceptable amlodipine salt. The pharmaceutically acceptable acid adduct is formed from an acid that forms a nontoxic acid adduct including a pharmaceutically acceptable anion, such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, lactate, tartrate, citrate or gluconate.
As distinct from salts of racemic amlodipine, almost none of which form hydrates, pharmaceutically acceptable salts of S-(−)-amlodipine are in the most part in the form of hydrates.
Korean Patent Laid-Open Publication No. 10-2005-37498 describes hydrophilic S-(−)-amlodipine salts or hydrates thereof and pharmaceutical compositions comprising the same. Examples of the hydrates of S-(−)-amlodipine salts include S-(−)-amlodipine benzenesulfonatedihydrate, S-(−)-amlodipine acetate monohydrate, S-(−)-amlodipine aspartate dihydrate, S-(−)-amlodipine tartrate dihydrate, S-(−)-amlodipine sulfate dihydrate, and S-(−)-amlodipine hydrobromide monohydrate.
Korean Patent Laid-Open Publication No. 10-2004-23474 discloses crystalline S-(−)-amlodipine nicotinate dihydrate and a preparation method thereof.
For use in pharmaceutical formulations, S-(−)-amlodipine salts must meet physical and chemical standards: 1) non-hygroscopicity, 2) high solubility, 3) high thermal stability, 4) high photostability and 5) low viscosity. In addition, requirements of acids suitable for use in pharmaceutically acceptable salts include non-pharmaceutical properties, harmlessness, and processing feasibility.
Currently commercially available is S-(−)-amlodipine besylate, which is in the form of 2.5 hydrate (water content: 7.5%). The high water content requires precise water control and scrupulous care for the preparation and storage of S-(−)-amlodipine.
As such, salts in a hydrous form suffer from disadvantages in that they are difficult or inconvenient to manage because their hydration varies depending on processing conditions, are hygroscopic, and are inferior in thermal stability to those in anhydrous forms. When processed into pharmaceutical formulations, hydrous salts show high viscosity.
*Existing in the form of hydrates, most currently used S-(−)-amlodipine salts are difficult to formulate into pharmaceutical preparations.
Therefore, there is a need for pharmaceutical salts of S-(−)-amlodipine that are imparted with physical properties good enough to overcome the problems encountered in the prior art.